Inside the Clinic: Acute Graft-versus-Host Disease - Episode 12
Joseph Antin, MD: So, Corey, I think relevant to this discussion is, “What are the grading systems that are utilized?” There are several grading systems. They are somewhat in evolution, and it’s a relevant adjunct to the biomarker discussion.
Corey S. Cutler, MD, MPH, FRCPC: There are 2 dominant grading systems that are used today. One is called the modified consensus scoring system, and that’s been in use for more than 20 years now.The individual organ stages are consistent across all the grading systems. But the newer Mount Sinai Hospital approach, or MAGIC [Mount Sinai Acute GVHD International Consortium] organ staging and grading system, slightly changes the overall grouping of the individual diseases and does incorporate the number of bowel movements for intestinal graft-versus-host disease (GVHD), so it allows a slightly more accurate way of grading and staging individuals. What’s important to recognize is that individual organ grades and stages actually predict outcome, and that’s why we use organ grading and staging so that we can enroll patients in clinical trials. We can speak to each other as clinicians and have meaningful discussions about stage and grade and be able to compare patients across studies.
Now we already touched on the risks for GVHD. You mentioned a few, such as the stem cell source. Do you want to elaborate on a couple more known risk factors for GVHD?
Joseph Antin, MD: Absolutely. I mentioned stem cell source. So peripheral blood stem cells, which have more T cells in them than bone marrow stem cells, are associated with a somewhat higher risk of GVHD, although…primarily chronic rather than acute disease. There are probably 10 fold more T cells in a peripheral blood stem cell product than there are when the bone marrow is collected directly from the iliac crest.
Other associations are, of course, with histocompatibility. So HLA antigen mismatched or HLA allele mismatched transplants are associated with more GVHD than those that are thought to be fully matched.
It used to be thought that the age of the recipient was important. It probably is certainly different between adults and children, but there’s no linear association with age. However, donor age does seem to be associated with a higher risk of GVHD. So older donors are associated with a higher risk. There are some associations with viral infections, such as CMV [cytomegalovirus] seropositivity and things of that nature. The GVHD prophylactic regimen that’s used is critically important. Some regimens are associated with a higher risk of GVHD than others. And what else?
Corey S. Cutler, MD, MPH, FRCPC: Well I think it’s important actually that you touched on the prophylactic regimen, so maybe we can chat about that for a minute. All patients require some form of prophylaxis against GVHD. Most of us use pharmacologic prophylaxis, and the standard in North America still is a drug such as tacrolimus or cyclosporin in conjunction with methotrexate. There are alternative preventative regimens that are out there. We’ve pioneered the use of tacrolimus and sirolimus. And, of course, in lower intensity transplant regimens we sometimes substitute methotrexate for mycophenolate [mofetil], although the results don’t seem to be as promising.
There’s also a whole other T-cell depletion route where you can either pharmacologically or physically manipulate the graft and take away the T cells that are known to cause GVHD or give the patient medications that eliminate the T cells, such as anti-thymocyte globulin or alemtuzumab. But it’s important to recognize that the rates of GVHD that we see are despite the use of GVHD prophylaxis.
Joseph Antin, MD: And a critical thing to realize about GVHD prophylaxis, at least with respect to T-cell depletion, is that there is a positive component to GVHD. We refer to this as GVL, or graft versus leukemia.
So to some extent, depending on how the conditioning regimen is administered, the conditioning regimen contributes a very substantial proportion of the anticancer effect of transplantation, but not the whole thing. And so part of the anticancer effect of transplantation is an immunological recognition of the malignancy by the donor immune system, and we call this GVL. In reduced intensity transplants, which are typically performed in older people or people with comorbidities, it’s the entire story.
If you take all of the T cells out, then you, by virtue of eliminating all of the effector cells, will get no GVL. So we do know that for those diseases that are very sensitive to this type of immunological control, the GVHD prophylaxis regimen has to be carefully considered in advance so that you don’t throw out the baby with the bathwater.
Transcript Edited for Clarity